Studies of the binding properties of opioid drugs and peptides at specific sites in the brain and other organs have suggested the existence of several types of opioid receptors. In the central nervous system (CNS), good evidence has been demonstrated for at least three categories of opioid receptors: .mu. .kappa. (mu), k (kappa) and .delta. (delta). Nalorphine, W. R. Martin, Pharmacol. Rev., 19, 463-521 (1967), and a series of benzomorphans, W. R. Martin, et al., J. Pharmacol. Exp. Ther., 197, 517-532 (1976), were reported to display unusual pharmacological properties dissimilar to morphine, yet blocked by selective opioid antagonists. The existence of multiple subtypes of opioid receptors is of considerable interest as it suggests the possibility of separating the desirable (analgesic and psychotherapeutic) and the undesirable (abuse potential) effects of opioids.
Indeed, compounds that are agonists for k receptor have shown strong analgesia without opioid side effects such as dependence liability, respiratory depression, and constipation. The prototype of such compounds is U-50,488, trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)cyclohexyl]benzeneacetam ide, which is described in U.S. Pat. No. 4,115,435, and reported by P. F. VonVoigtlander, et al., J. Pharmacol Exp. Ther., 224, 7 (1983). This compound is stated to exhibit analgesic actions in a variety of assays, such as thermal, pressure and irritant, in mice and rats.
Spirocyclic analogs of U-50,488 are disclosed in U.S. Pat. Nos. 4,359,476, 4,360,531, and 4,438,130, as analgesic compounds having low physical dependence liability in humans. Examples of these derivatives are trans-3,4-dichloro-N-methyl-N-[7-(pyrrolidin-1-yl)-1,4-dioxaspiro[4.5]dec- 6-yl]benzeneacetamide; trans-3,4-dichloro-N-methyl-N-[7-(pyrrolidin-1-yl)-1,4-dioxaspiro[4.5]dec- 8-yl]benzeneacetamide; and (.+-.)-(5-a-7-a-,9.beta.)-3,4-dichloro-N-methyl-N-[7-(pyrrolidin-1-yl)-1-o xaspiro[4.5]dec-8-yl]benzeneacetamide. Omega- (Hydroxy-, Ether and Ester)-Alkyl-2-Amino-Cycloalkyl and Cycloalkenyl Amides active as analgesics are disclosed in U.S. Pat. No. 4,632,935.
Substituted trans-1,2-diaminocyclohexylamide compounds such as trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexylbenzo[b]thiophene- 4-acetamide are disclosed in U.S. Pat. No. 4,656,182. Naphthaleneyloxy-1,2-diaminocyclohexyl amide compounds active as analgesics are disclosed in U.S. Pat. No. 4,663,343.